EP0165636A1 - Verfahren zur Herstellung von Azetidinderivaten und Zwischenprodukte - Google Patents

Verfahren zur Herstellung von Azetidinderivaten und Zwischenprodukte Download PDF

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Publication number
EP0165636A1
EP0165636A1 EP85200881A EP85200881A EP0165636A1 EP 0165636 A1 EP0165636 A1 EP 0165636A1 EP 85200881 A EP85200881 A EP 85200881A EP 85200881 A EP85200881 A EP 85200881A EP 0165636 A1 EP0165636 A1 EP 0165636A1
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EP
European Patent Office
Prior art keywords
acid
formula
azetidine
bis
group
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EP85200881A
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English (en)
French (fr)
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EP0165636B1 (de
Inventor
Margaretha Johanna De Nie-Sarink
Ronald Frank Mason
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shell Internationale Research Maatschappij BV
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Shell Internationale Research Maatschappij BV
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Application filed by Shell Internationale Research Maatschappij BV filed Critical Shell Internationale Research Maatschappij BV
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

Definitions

  • This invention relates to a process for preparing azetidine derivatives, more specifically azetidine-3-carboxylic acid and salts thereof, and to certain intermediates in the process.
  • azetidine-3-carboxylic acid and salts thereof may be prepared by a process involving a reaction step in which a 3,3-bis(hydroxymethyl)-azetidine is treated with nitric acid.
  • a process for preparing azetidine-3-carboxylic acid or a salt thereof which comprises treating a compound of formula wherein R represents a hydrogen atom or a group of formula R 1 R 2 CH- wherein R 1 and R 2 are independently selected from hydrogen, alkyl (preferably C 1-6 alkyl) and optionally substituted aryl (preferably C 6-12 aryl) moieties, with nitric acid and subjecting the resulting product to acid conditions to produce an acid-addition salt of formula I, and thereafter, if desired, converting the acid addition salt to the free acid or another salt of the acid of formula I.
  • Optional substituents in an aryl moiety include one or more substituents selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, halo, nitro and (C 1-6 alkoxy)carbonyl moieties.
  • R 1 and R 2 in the group R 1 R 2 CH- is hydrogen.
  • R in formula II represents a hydrogen atom or a group of formula R 1 CH 2 - wherein R 1 represents hydrogen, a C 1-3 alkyl group or a phenyl group.
  • the compound of formula II may conveniently be treated with nitric acid at a temperature in the range 35°C to the reflux temperature of the reaction mixture, conveniently a temperature in the range 40 to 85°C. Temperatures in the range of 45 to 60°C are very effective.
  • the concentration of nitric acid used in the treatment of the compound of formula II be at least 40%w/w. Conveniently the concentration of the nitric acid used is in the range 50 to 65%w/w.
  • the resulting product may, or may not, be isolated prior to the step of subjecting it to acid conditions.
  • the step of subjecting the resulting product to acid conditions comprises treating the product with an aqueous acid selected from nitric, formic, acetic, hydrohalic (e.g. hydrochloric) and sulphuric acids. If nitric acid is used, its concentration is preferably 30%w/w or less.
  • an aqueous acid selected from nitric, formic, acetic, hydrohalic (e.g. hydrochloric) and sulphuric acids. If nitric acid is used, its concentration is preferably 30%w/w or less.
  • the resulting product is preferably subjected to acid treatment at temperatures above 80°C, more preferably above 90°C. Conveniently the resulting product is subjected to acid conditions at the reflux temperature of the reaction mixture.
  • the compound of formula I will generally exist as an acid-addition salt. If the acid is formic acid, it may be driven off with water when an aqueous solution is evaporated to dryness, to liberate the free acid. In other cases, acid-addition salts can readily be converted to the free acid, or to other acid-addition salts by conventional known methods.
  • the invention also comprehends azetidine-3-carboxylic acid or a salt thereof whenever prepared by the process of the invention.
  • Intermediates which may be produced in the process of the invention include azetidine-3,3-dicarboxylic acid, 1-nitroso- azetidine-3,3-dicarboxylic acid and 1-nitrosoazetidine-3-carboxylic acid.
  • azetidine-3,3-dicarboxylic acid is subject of Applicants' copending U.K. patent application No. 8415614.
  • the present invention includes as novel compounds the 1-nitroso-azetidine-3-carboxylic acid derivatives of formula or salts thereof, wherein R 3 is hydrogen or a group of formula COOH.
  • 3-bromomethyl-3-hydraxymethyl oxetane (7.5g; 41mmol) was taken up in 25% (w/w) aqueous ammonia (100ml) and the mixture was stirred for 16 hours in an autoclave at 80°C. After evaporation of the aqueous ammonia, 48% (w/w) aqueous hydrcbrcmic acid (10ml) was added to the residue and the resulting solution was stirred at 60°C. After 2 hours the aqueous hydrobromic acid was evaporated off, 25% (w/w) aqueous ammonia (75ml) was added to the residue, and the resulting solution was stirred at 60°C.
  • 3,3-bis(hydroxymethyl)azetidine may be prepared by debenzylation of 3,3-bis(hydroxymethyl)-1-benzylazetidine using hydrogen over palladium on carbon catalyst in methanol.
  • 3,3-Bis(hydroxymethyl)-1-nethylazetidine was prepared by a process similar to that of Example 2 using methylamine instead of ammonia.
  • 3,3-Bis(hydroxymethyl)-1-ethylazetidine was prepared by a process similar to that of Example 2 using ethylamine instead of ammonia.
  • 3,3-bis(hydroxymethyl)-1-isopropylazetidine was prepared by a process similar to that of Exanple 2 using isopropylamine instead of ammonia.
  • Example 3 3,3-bis(hydroxymethyl)-1-methylazetidine, and of Example 4, 3,3-bis (hydroxymthyl)-1-ethylazetidine, were oxidised under the conditions of Example 8(i), and in each case the product was 1-nitrosoazetidine-3,3-dicarboxylic acid.
  • Example 8(ii) 1-Nitrosoazetidine-3,3-dicarboxylic acid was subjected to acid treatment following procedures comparable with that of Example 8(ii). Experimental conditions and results are given in Table 3 following. Comparative Example A demonstrates that acid conditions are necessary for full conversion, but demonstrates that 1-nitrosoazetidine-3-carboxylic acid is an intermediate in conversion of 1-nitrosoazetidine-3,3-dicarboxylic acid to azetidine-3-carboxylic acid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP85200881A 1984-06-19 1985-06-04 Verfahren zur Herstellung von Azetidinderivaten und Zwischenprodukte Expired EP0165636B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT85200881T ATE36318T1 (de) 1984-06-19 1985-06-04 Verfahren zur herstellung von azetidinderivaten und zwischenprodukte.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB848415615A GB8415615D0 (en) 1984-06-19 1984-06-19 Preparing azetidine derivatives
GB8415615 1984-06-19

Publications (2)

Publication Number Publication Date
EP0165636A1 true EP0165636A1 (de) 1985-12-27
EP0165636B1 EP0165636B1 (de) 1988-08-10

Family

ID=10562649

Family Applications (1)

Application Number Title Priority Date Filing Date
EP85200881A Expired EP0165636B1 (de) 1984-06-19 1985-06-04 Verfahren zur Herstellung von Azetidinderivaten und Zwischenprodukte

Country Status (9)

Country Link
US (1) US4665197A (de)
EP (1) EP0165636B1 (de)
JP (2) JPS6112658A (de)
AT (1) ATE36318T1 (de)
BR (1) BR8502885A (de)
CA (1) CA1223269A (de)
DE (1) DE3564263D1 (de)
GB (1) GB8415615D0 (de)
ZA (2) ZA854545B (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0199413A3 (de) * 1985-04-16 1987-05-06 Shell Internationale Researchmaatschappij B.V. Verfahren zur Herstellung von Azetidinderivaten und Zwischenprodukte
EP0221579A1 (de) * 1985-09-30 1987-05-13 Shell Internationale Researchmaatschappij B.V. Verfahren zur Herstellung einer Azetidin-3-carbonsäure oder ihrem Salz

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8627493D0 (en) * 1986-11-18 1986-12-17 Shell Int Research Catalytic hydrogenolysis
US4867738A (en) * 1987-09-14 1989-09-19 International Technidyne Corporation Apparatus and methods for utilizing autotransfusion systems and related equipment
EP0607374B1 (de) * 1992-06-30 1999-04-07 Pohang Iron & Steel Co., Ltd. Neue cyclische lipidderivate als potente paf-antagonisten
US5700817A (en) * 1992-06-30 1997-12-23 Pohang Iron & Steel Co., Ltd. Cyclic lipid derivatives as potent PAF antagonists
AU5798996A (en) * 1995-05-15 1996-11-29 Sachs, Michael C. Adnaz, compositions and processes
CN106632395B (zh) * 2016-11-30 2018-09-21 辽宁大学 一种螺环氨基酸酯类化合物及其制备方法和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1479735A (fr) * 1966-05-12 1967-05-05 Novomoskovsky Anilinokrasochny Procédé de fabrication de l'acide oxalique

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1169027A (en) * 1966-11-19 1969-10-29 Beecham Group Ltd Azetidine Derivatives
CA1261858A (en) * 1979-11-16 1989-09-26 Barry R.J. Devlin Method of producing male sterility in plants
GB8300860D0 (en) * 1983-01-13 1983-02-16 Shell Int Research Azetidine compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1479735A (fr) * 1966-05-12 1967-05-05 Novomoskovsky Anilinokrasochny Procédé de fabrication de l'acide oxalique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TETRAHEDRON, vol. 32, no. 22, 1976, pages 2689-2692, Pergamon Press, GB; R.H. FISH et al.: "Gas phase protonolysis reactions chemical ionization mass spectrometry of N-nitrosamines" *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0199413A3 (de) * 1985-04-16 1987-05-06 Shell Internationale Researchmaatschappij B.V. Verfahren zur Herstellung von Azetidinderivaten und Zwischenprodukte
EP0221579A1 (de) * 1985-09-30 1987-05-13 Shell Internationale Researchmaatschappij B.V. Verfahren zur Herstellung einer Azetidin-3-carbonsäure oder ihrem Salz

Also Published As

Publication number Publication date
ATE36318T1 (de) 1988-08-15
EP0165636B1 (de) 1988-08-10
ZA854545B (en) 1986-02-26
CA1223269A (en) 1987-06-23
DE3564263D1 (en) 1988-09-15
US4665197A (en) 1987-05-12
GB8415615D0 (en) 1984-07-25
ZA854582B (en) 1986-04-30
BR8502885A (pt) 1986-02-25
JPS6112690A (ja) 1986-01-21
JPS6112658A (ja) 1986-01-21

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